ClinVar Miner

Submissions for variant NM_005902.4(SMAD3):c.394A>G (p.Thr132Ala) (rs371876622)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000200310 SCV000250798 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing p.Thr132Ala (ACA>GCA): c.394 A>G in exon 2 of the SMAD3 gene (NM_005902.3). A variant of unknown significance has been identified in the SMAD3 gene. To our knowledge, the T132A variant has not been published as a mutation nor as a benign polymorphism. The T132A variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The T132A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported in association with TAAD or a related disorder, suggesting this region of the protein may be tolerant to change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-1,TAAD
GenomeConnect, ClinGen RCV000845020 SCV000986853 not provided Loeys-Dietz syndrome 3 no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 08/23/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000541741 SCV000658881 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-07-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 132 of the SMAD3 protein (p.Thr132Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs371876622, ExAC 0.004%). This variant has not been reported in the literature in individuals with SMAD3-related disease. ClinVar contains an entry for this variant (Variation ID: 213803). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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